The lysosomal disorders (LD) are a group of approximately 70 inherited metabolic conditions resulting from defects in lysosomal function; usually deficiency of a single enzyme required for the metabolism of lipids, glycoproteins, or mucopolysaccharides. Collectively, LD are not especially rare; estimates suggest that approximately 1:5,000 newborns will be affected with one identified LD. Individually however, each disorder occurs with a much lower frequency. Assuming that 180 individuals per 1 million live births will be affected with an LD, extrapolation incidences range from Gaucher at 25 per 1 million births to 7 per 1 million births for GM1- gangliosidosis; other LD are much rarer still. Most LD are monogenetic disorders caused by a mutation in a single gene and follow an autosomal recessive inheritance pattern, although a few are X-linked recessive. Although each LD results from a unique gene mutation, at the biochemical level they share a common characteristic?the inability to clear metabolic substrate from the lysosome. Presenting symptoms vary widely among the disorders and are modified by age of onset and severity (most LD present as either a severe or attenuated phenotype); beyond categorization as severe or attenuated, a more specific genotype/phenotype correlation has not been feasible. To date, about a dozen or so LD have therapeutic options, but apart from MPS I, which has been shown amenable to stem cell transplant, LD drug therapies are not particularly effective in those conditions with neurologic dysfunction. And while new treatments, be it next generation drug therapy, gene therapy, or other gene editing techniques, are essential to improve outcomes for those affected with LD, early detection is critical in order for a person with an LD to hope for a normal life. In the past three decades, lysosomal diseases have been a test bed for some of the most innovative therapeutic modalities. In the past 9 years of NIH funding, the LDN has accelerated knowledge acquisition in the field?with 95 NCBI cited publications?and furthered the development of therapeutic options. For the next 5 years, the overarching thematic goals of the LDN are: clinical trial readiness, newborn screening, long-term outcomes, and global reach. We will advance these goals through clinical investigation via 5 longitudinal studies focused on elucidation of disease pathology by (a) CRIM status and immune tolerance induction in Pompe disease, (b) cardiac and kidney pathology in Fabry disease, (c) multi-system survey (cardiac, developmental, skeletal, QOL) in the mucopolysaccharidoses, and (d) MRI and biomarker development as outcome measures for the gangliosidoses. The fifth project is a survey study designed to catalog both the odyssey individuals go through before reaching a proper diagnosis and the effectiveness of therapeutics at allowing individuals with lysosomal disease (specifically treated MPS) to live an independent life. Every participant who enrolls in an LDN project is expected to complete the survey studies. Biostatistical analysis assures relevant statistical models for each project.